N, n&#39;-diarylamidines



Patented Dec. 5, 1944 UNITED $14125 NLN'JHAIWINES Stamford, Coma,

andDanielLNllI- American a-lgnorsto amid Company, New York, N. Y aeorporaiion olllaine NoDrawing. Applicationlhlflfl. ierlalhlaflm "lemma (asst-sen This invention relates to a new method oi preparing N,N-diarylamidines.

Although some oi the N,N'-diarylamidines whose preparation is demrlbed herein are new compounds, these amidines are, as a class, broad- 1y old. Known processes of preparing N,N'-diarylamidines have required the use oi such reagents as phosphorus halides or anhydrous H01. In addition to the obvious disadvantages of using such' reagents, the pr employing them have not been entirely satisfactory because of low yields, the necessity for working at high or at very low temperatures. and the chemical disintegration or the reactants and/or product by these reagents. Because of this latter fact. the previously known methods of preparing N, N'-diarylamidines were not suitable for the preparation of the more complex amidines. Our process, on the other hand, gives good yields of N,N'-diaryiamidines at moderate temperatures in a comparatively short length oi time, using cheap, readily available and easily handled reagents. Our process is also particularly advantageous in being suitable for the preparation 01' many different iwpes and kinds of N,N'-diarylamidines including those complex amidines which can not be prepared by previously described methods.

The N,N'-diarylamidines which may be prepared by our process have the general formula:

in which B may be an aliphatic, aromatic or alicyclic group, which may contain nitrogen, oxygen and sulfur linkages as well as substituents oi various types and kinds, and R. and B." may be the same aryi radicals. R, R and B" may have various substituent groups such as, CONH:, COOH, C0, --SO:NH=, -OR, -N'Ra, ll0:, -SO:|H, halogen, alkyl, aryl. etc.

The above N,N'-diarylamidines are prepared by our new process by reacting an acyl dicyandiamide with a primary aryl amine in the presence of an acid having a dissociation constant of at least 1x10. Although we'have not definitely determined how N,N'-diarylamidines are formed by our process it appears most likely, at present, that the following reactions are involved.

40 diamide is formed.

In support of this, we have isolated and identified the product of the first equation. Since it is possible that other unknown intermediate reactions may take place, however, we do not wish to be bound by any theory or supposed course of reaction. Many of the compounds prepared by our process have been compared with known N31- diarylamidines prepared by other p and it has been established as a fact that our reaction results in the formation of N,N'-diarylamidinea Chemical analysis and other chemical and physical properties have proven others to be as described.

we have found that any primary aromatic amine may be reacted with an acyl dicyandiamide in accordance with the above equation to yield N,N'-diarylamidines. The aryl group may have a as wide variety oi substituents attached thereto as stated above and as shown in the specific examples which follow. Representative of such primary aryl amines are aniline, toluidine, phentidine. suli'aniiamide, p-phenylenediamine, u-naphthylamine, p-aminoacetanilide, sultanilic acid, 4-

amino-1,3,5-dimethylaniline, p bromaniline, etc. Of course,the acidsalts ottheseaminesmayalso be employed.

The acyl dicyandiamides employed by us may be prepared by mixing an acylating agent such as an ti are benzoyldicyandiamide, acetyldicyandiamide,

caproyldicyandiamide, lauroyldicyandiamide, sebacyl-bis-dicyandiamide, adipyl bis dicyandiamide. p-nitrobensoyldicyandiamide, u-carboxypropionyldicyandiamide, o carbonbensoyldicyandiamide, p-hydroiwbenzoyldicyandiamide,

ethoxypropionyldicyandiamide, naphthenyldlcyandiamide, hexahydrotoiyldicyandiamide, a-bl'O- mocaproyldicyandiamide, fl-io-dichlorostearyldi a o L, g I E a cyandiamide, p butylaminopropionyldicyandia mid and others.

As stated before, any acid, either organic or inorganic, having a dissociation constant of at least l lmay be employed by us in our reaction. Among such acids are hydrochloric, sulfuric, sulfurous, nitric, phosphoric, sulfanilic, valeric. acetic, benzoic, e-chlorpropionic, formic and others. Acid salts such as aniline hydrochloride, s-naphthylamine sulfate, etc. may also be used if desired.

The reaction is ordinarily carried out in the presence of a solvent to facilitate contact of the reagents and simplify the recovery 01' the product. Any inert solvent such as water, alcohol, acetone, dioxane, monoethyl ether of ethylene glycol and the like may be used alone or in admixture. It is not necessary that water he present in the reaction mixture. The amount of solvent is not critical, enough being used to dissolve the reactants and allow easy separation of the reaction product.

Although the reaction will, in some cases, take place at room temperature, particularly after a long period of time, the reaction is best conducted at elevated temperatures of from about 50 to 110 C., or more. The reaction is normally complete within minutes to 2 or 3 hours, the time depending upon both the temperature 01' the reaction mixture and the particular reagents employed.

Most of the N,N'-dlary1amidines are insoluble in alkaline solution and they may be readily separated from the reaction mixture by suspending the latter in water, and then adding an alkali, such as sodium hydroxide, potassium hydroxide, etc. to the solution to precipitate the N,N'-diarylamldine. This procedure is advantageous in that guanides which are sometimes formed in small amounts as side reaction products are soluble in alkaline solutions and may be separated from the amidine in this way. 01. course, if the product is not required to have an exceptionally high purity, these purification steps may be omitted.

Th proportions of reactants may vary rather widely. For each mole of the primary aromatic amine, we may use from about one-half to two moles of acid and one-half to two moles, or more, of the acyl dicyandiamide. However, there appears to be no particular reason for using a larger excess of any oi the reactants beyond that required by the reaction equations given above.

Our invention will now be illustrated in greater detail by means of the following examples. It should be understood that these eiamples are merely illustrative and are not to be construed as limiting our invention to the particular reactants, proportions and reaction conditions described. NlP-diaryiamidines, other than those specifically described, have been prepared by us in good yields under conditions differing from those specifically set forth in these examples but falling within the scope of our invention as described hereinabove.

Exams 1 NJW-diphenillbutinomidine To a solution composed of 290 a. (3.5 moles) of dicyandiamide, 560 cc. of 50% NaOH solution (7.0 moles), 100 cc. of water and 500 cc. of acetone was added slowly at 5 C., 240 g. (2.26 moles) oi butyryl chloride. After further stirring for a few minutes, the reaction mixture was acidified to a pH of about 5.5 with acetic acid whereupon butyryldicyandiamide was precipitated from soiution. The product was filtered, washed with cold water and air dried.

10.2 g. (0.11 mole) oi aniline and 8.5 cc. of concentrated hydrochloric acid (0.1 mole) were dissolved in 15 cc. of methanol and the solution heated approximately C. To the heated solution there was added, with stirring, over a period of 0.5 to 1 hour, 7.7 g. (0.05 mole) of butyryldicyandiamide. The heating was then continued for 15 minutes after which the solution was cooled, filtered, diluted with water and made alkaline. A gum-like material which precipitated when the solution was made alkaline was Nildiphenylbutyramidine. This product was further purified by dissolving it in dilute HCl, adding decoiorizing charcoal to the solution, filtering, and making the filtrate strongly alkaline with NaOH while stirring in an ice bath. The amidine separated as a gum-like material which gradually solidified on continued stirring. N,N'-diphenylbutyramidlne is prepared by this process in good yields. The amidine is soluble in acetone and dilute HCl and has a melting point of 106-108 C.

Exmru 2 The above experiment was repeated using onehaif molecular portion of I-ICl. The N,N'-diphenylbutyramidine was obtained as before in practically the same yield.

Exmru 3 The process of Exampl 1 was repeated using 0.1 mole of acetic acid in place oi HCl. N,N-diphenylbutyramidine was prepared by this process with fair yields.

Exurrts 4 A solution of 9.3 g. of aniline and 4.3 cc. of concentrated hydrochloric acid in 10 cc. of water and 10 cc. of acetone was prepared and heated to approximately 65 C. To the heated solution there was added slowly 7.7 g. of butyryidicyandiamide. After heating the reaction mixture for 55 minutes, the solution was cooled, filtered, diluted with water and made alkaline. N,N'-diphenylbutyramidine precipitated. The amidine was further purified as described in Example 1 and eventually recovered in a yield 01' 87% 01' theoretical.

Exnuruib A solution 014.7 g. of aniline and 2.2 cc. of concentrated hydrochloric acid in 15 cc. of dioxane was heated to about 63 C. To this heated solution there was added 7.7 g. of butyryldicyandiamide in small portions over a period of from 0.5 to 1 hour. After the reaction mixture had been heated for 90 minutes, it was cooled, filtered, diluted with water and made alkaline as in the preceding examples. N,N'-diphenylbutyramidine was recovered as before in a yield of 74% based on th amount of aniline used.

Erma! 6 A mixture composed oi 4.7 g. of aniline, 7.2 g. of aniline hydrochloride and 30cc. of dioxane was heated to 68 C. and 7.7 g. of butyryldicyandiamide added slowly thereto. After heating the reaction mixture for 25 minutes at 60 0., the solution was cooled. filtered, diluted with water and made alkaline. The precipitated N,N'-diphenylbutyramidine was obtained in a yield of 46% of theoretical.

idine was obtained in fair yields.

mural 8 N,N'-diphenvloaleramidi1te K A mixture or 100 oi dicyandiamide, 214 cc. oi 60% potassium hydroxide and 300 cc. of acetone was prepared and cooled to C. 92.9 a. or valeryl chloride was added to the solution slowly with stirring. The reaction mixture was then carefully acidified to a pH oi about 5.5 whereupon valeryldicyandiamlde was precipitated. The product was filtered, washed with cold water and air dried.

To a solution of 9.1 g. of aniline, 12 cc. of glacial acetic acid and cc. of water was added'in portions during one-hall hour 8.4 3. cl valeryldic'yandlamlde. The reaction mixture was'heated at 72 C. for a total of 2 hours. The clear solution was diluted with water and made alkaline. The precipitated gum-like material which formed was filtered from solution. dissolved in dilute acetic acid and the solution again made alkaline with NaOH. The precipitated N.N'-diphenylvaleramidine. upon recrystallization from a methanol-water mixture, was found to have a melting point of 90-91 C. and was soluble in dilute HCl and methanol.

Exams: 9

N.N'-diflienvllauramidine A solution of 10 g. 01 aniline, 4.3 cc. of concentrated (87%) hydrochloric acid and 30 cc. of methanol was heated to refluxing and 18.3 I. of lauryldicyandiamide added thereto over a period of 40 minutes. After minutes additional heatins. the solution became clear and a new precipitate formed. The reaction mixture was diluted to 200cc. with water and made alkaline with NaOH. N,N'-diphenyllauramidine was precipitated. Alter recrystallization from a methanolwater mixture, the compound was found to have a melting point 0! 92-94 C. and was insoluble in cold methanol. but dispersed in a dilute solution of hydrochloric acid.

Exams: 10 N,N'-diphenrl p-ethomropimmidine enema-i=0 0 assasoa was added thereto in one and one-half hours. The reaction mixture was then diluted with 000 cc. oi a 10% solution oi sodium chloride and then neutralised with acetic acid. s-onyldicyandiamlde was recovered by nitration.

A solution of 9.3 g. of aniline, 8.5 cc. oi concentrated acid. cc. of acetone and 10 cc. of water was heated to refluxing temperature and ii oi p-ethoxypropionyldlcyandiamide was'added slowly thereto. After heating the mixture for 2 hours, the solution was cooled and made alkaline with a solution of NaOH. N,N'-diphenyl I p-dine was recovered by filterhis the alkaline solution. Aiter recrystallization from a methanol-water solution. the product was found to have smelting point of 88-70 C. It was soluble in methanol and dilute hydrochloric acid. Chemical analysis 01' the product corresponded to N.N'-diphenfl p-ethoxypropionamidine.

Elma! ll Nfl'-di-p-ethosy-p-ethocvmlommidlne A solution oi 13.7 s. of phenetldine, 6 cc. of concentrated hydrochloric acid, 30 cc. of acetone and 10 cc. of water was heated to 65 C. and 14.7 g. oi B-ethoxypropiondicyandiamide added thereto. After heating the reaction mixture for 2 hours, it was filtered, diluted with water and made strongly basic with NaOI-l. The dark colored gummy product which precipitated was slightly impure NJV-di-p-ethoxy-p-ethompropionamidine. The amidine was treated with about cc. oi 5% H61, the liquid decanted and the gum dissolved in water and treated with activated charcoal. The solution was filtered and made alkaline whereupon the amidine was again precipitated. It was crystallized trom a methanolwater mixture. It had a melting point of 45-48 C. and was soluble in methanol but insoluble in 5% H01.

. minus 12 MNW-p-sullonamidophermlcaproamidtne p ounc=nsomm H-ILQEOsNH:

N,N'di-p-acetcminophenulcaproamldin CIHIIOBN n-XLQrmo 0 cm NHOOCH:

A mixtureosl 00.8 g. oi 50$ p-aminoacetanilide, 9.85 cc. of hydrochloric acid, 100 cc. oiacetoneandlflmofwaterwasheatedtoflv C. Tothismixturewasadded 18.5 g. ofcaproyldicyandiamideinthreeportions durlngthecqurae oi an hour. The amino hydrochloride dissolved as the acyl dicyandismide was added and the iinalsolutionwasciear. Aiteronemonehour or heating N,H'-di-p-acetphenvlcaproamidine was recovered by diluting the cooled solution withwaierandaddinaencssaalkali. 'Ihecrystalline amidine was dissolved in dilute acid. treatedwithactivatedcharconfiltered androrecipitated with alkali. Asampls of tin amidine recrystallized from methanol had a melting point of 105-105 C.

mm 14 N,N'-di-p-sa1fopnenylca9romidine A solution of 20.9 g. of suifanilic acid dihydrate, '10 cc. oi water and 50 cc. of acetone was heated to refluxing and 11 g. of caproyldicyandiamide added in five equal portions thereto during the course of one hour. After two more hours heating at refluxing temperature, the reaction mixture was cooled, diluted with water and flitered. The crude solid obtained upon filtration was extracted twice with 250 cc. portions of hot water to remove any unreacted suifanilic acid. The insoluble residue was suspended in 150 cc. oi water containing 3 cc. 0! concentrated hydrochloric acid and the mixture filtered The insoluble fraction was 8,11 '-di-p-sulfophenylcaproamldine, which had a melting point or 225-228 0., was very insoluble in hot water and decomposed in alkali.

Exnl'm-I 15 N,N'-di-p-cthouflienyloaleramidine A solution of 13.7 g. of p-phenetidine, 4.5 cc. of concentrated hydrochloric acid, cc. of acetone and 10 cc. 0! water was heated to refluxing temperature and 9.24 g. of valeryidicyandlamide added slowly thereto. The solution was then diiui'ed with water. cooled and made alkaline. The product, N,N'-di-p-ethoxyphenylvaleramidine was recovered by filtration. After one crystalli tion from a methanol-water mixture, the product had a melting point of 98-100 C. Alter three more recrystallizations from methanol-water the melting point was unchanged. I

manna 16 N,N'-di-o-tolylosleramidine CJL-IAQ Q A nlution or 10.! s. of o-toiuidine, 4.25 cc. or concentrated hydrochloric acid, 10 cc. of acetone OCHI Cent

assqsss ;j

ny-ac-u-almetnulpmvmummu A solution of 18.1 g. of 4-amlno-L3-dimethylbensene. 8.8 cc. of concentrated hydrochloric acid. 12 cc. of acetone and'12 cc. of water was heated to refiuxingtemperature and 15.4 g. at valeryldicyandiamide added thereto. After filter-ins the reaction mixture, diluting with water and adding excess alkali. N;N'-di-2.4-dimethylphenylvaleramldine was precipitated. A purified sam. ple of this product had a melting point of 01- 92 C. It was soluble in dilute hydrochloric acid and methanol.

Exams 18 N,N',N",N"'-tetraphenwlsdipamidine -c.m-c=N C 0 I N,N',N",N"'-tetraphenylsebocamidine 18.6 r. of aniline, as cc. oi concentrated bydrochloric acid, 5 cc. water and 15 .cc. of the monoethyi ether of ethylene glycol were heated to refluxing temperature and 18 g. of powdered sebacyldicyandiamide added during a period oi 5 minutes. After stirring for one hour. the clear brown solution was diluted to 400 cc. with water, acidified. and filtered. Addition or alkali to the filtrate precipitatedn slightly sticlw solid. Upon recrystallization twice from methanol, the prodnot was found to be N,N',N",N"'-tetraphsnyisebacamidine. The product had a melting point of 146-148 0., was fairly soluble in methanol and II llllhtly soluble in dilute H01.

Emu 20 NJV'-di-e-naphthulcaproamdme 14.5 g. of caproyldicyandiamide was added in portions to a solution of 16.5 g. of a-naphthylamine, 4.7 cc. of concentrated hydrochloric acid and 40 cc. of acetone. After heating for 2 hours at refluxing temperature, the clear solution was diluted with water and made alkaline. A precipitate of N,N-di-a-naphthylcaproamidine was obtained. The gummy product could not be crystallized from common solvents.

EXAMPLE 21 N ,N -diphenylbenzamidme A mixture of 18.8 g. of benzoyldicyandiamide, 9.3 g. of aniline and 8.5 cc. of concentrated hydrochloric acid were heated to an exothermic reaction on a steam bath and then for minutes more. The reaction mixture contained benzeguanide and N,N'-diphenylbenzamidine. The latter product was isolated by adding to the mixture, water and NaOH. The benzoguanide dissolved in this solution leaving the amidine as an insoluble residue. The solution was filtered and N,N'-diphenylbenzamidine recovered. Upon recrystallization of the latter from methanolwater solution, it was found to have a melting mint within the range 144-148 C. Chemical analysis of the product checked closely with the theoretical values for N,N'-diphenylbenzamidine.

We claim:

1. A method of preparing N,N'-diarylamldines Certificate of Correction Patent No. 2,364,593.

which comprises the step of mixing a primary aromatic amine, a carboxylic acyl dicyandiamide and an acid having a dissociation constant oi at least l 10- 2. A method of preparing N,N-diarylamidines which comprises the steps of mixing a primary aromatic amine, a carboxylic acyl dicyandiamide and an acid having a dissociation constant of at least 1 l0- and heating the mixture at temperatures within the range 50" C. to C. until an N,N'-diarylamidine is formed.

3. A method of preparing N,N'-diarylamidines which comprises the steps of mixing a primary aromatic amine, a carboxylic acyl dicyandiamide and an acid having a dissociation constant of at least l 15 and heating the reaction mixture at elevated temperatures for a period of time of from about 15 minutes to 3 hours.

4. A method of preparing N,N'-diarylamidines which comprises the steps of mixing a primary aromatic amine, a carboxylic acyl dicyandiamide, an acid having a dissociation constant of at least 1x10 and an insert solvent and heating the mixture at temperatures within the range of 50 C to 110 C. for a period of time 01' from about 15 minutes to 3 hours.

5. A method of preparing N,N'-diarylamidines which comprises the steps of mixing a primary aromatic amine with an aliphatic carboxylic acyl dicyandiamide, an acid having a dissociation constant of 1x 10-, and an inert solvent and heating the reaction mixture at an elevated temperature until an N,N-dlarylamidine is formed.

6. A method of preparing N,N'-diarylamidines which comprises the steps of mixing a primary aromatic amine with an aromatic carboxylic acyl dicyandiamide, an acid, having a dissociation constant 01' 1x10 and an inert solvent and heating the reaction mixture at an elevated temperature until an N,N'-diarylamidine is formed.

7. A method of preparing N,N-diarylamidines which comprises the steps of mixing in a solvent a carboxylic acyl dicyandiamide and an acid salt of a primary aromatic amine and heating the mixture until an N,N'-diarylamidine is formed.

JACK T. THURSTON. DANIEL E. NAGY.

December 5, 1944.

JACK T. THURSTON ET AL. It is hereby certified that error appears in the rinted specification of the above numbered patent req claim 3, for IXIS Hw with this correction the Patent Oifice.

correction as follows: 1X10"; and that the said therein that the same may conform to the record of the case in e 5, second column, line 16 otters Patent should be read Signed and sealed this 6th day of March, A. D. 1945.

[sun] LESLIE FRAZER,

Acting Commissioner of Patents.

Emu 20 NJV'-di-e-naphthulcaproamdme 14.5 g. of caproyldicyandiamide was added in portions to a solution of 16.5 g. of a-naphthylamine, 4.7 cc. of concentrated hydrochloric acid and 40 cc. of acetone. After heating for 2 hours at refluxing temperature, the clear solution was diluted with water and made alkaline. A precipitate of N,N-di-a-naphthylcaproamidine was obtained. The gummy product could not be crystallized from common solvents.

EXAMPLE 21 N ,N -diphenylbenzamidme A mixture of 18.8 g. of benzoyldicyandiamide, 9.3 g. of aniline and 8.5 cc. of concentrated hydrochloric acid were heated to an exothermic reaction on a steam bath and then for minutes more. The reaction mixture contained benzeguanide and N,N'-diphenylbenzamidine. The latter product was isolated by adding to the mixture, water and NaOH. The benzoguanide dissolved in this solution leaving the amidine as an insoluble residue. The solution was filtered and N,N'-diphenylbenzamidine recovered. Upon recrystallization of the latter from methanolwater solution, it was found to have a melting mint within the range 144-148 C. Chemical analysis of the product checked closely with the theoretical values for N,N'-diphenylbenzamidine.

We claim:

1. A method of preparing N,N'-diarylamldines Certificate of Correction Patent No. 2,364,593.

which comprises the step of mixing a primary aromatic amine, a carboxylic acyl dicyandiamide and an acid having a dissociation constant oi at least l 10- 2. A method of preparing N,N-diarylamidines which comprises the steps of mixing a primary aromatic amine, a carboxylic acyl dicyandiamide and an acid having a dissociation constant of at least 1 l0- and heating the mixture at temperatures within the range 50" C. to C. until an N,N'-diarylamidine is formed.

3. A method of preparing N,N'-diarylamidines which comprises the steps of mixing a primary aromatic amine, a carboxylic acyl dicyandiamide and an acid having a dissociation constant of at least l 15 and heating the reaction mixture at elevated temperatures for a period of time of from about 15 minutes to 3 hours.

4. A method of preparing N,N'-diarylamidines which comprises the steps of mixing a primary aromatic amine, a carboxylic acyl dicyandiamide, an acid having a dissociation constant of at least 1x10 and an insert solvent and heating the mixture at temperatures within the range of 50 C to 110 C. for a period of time 01' from about 15 minutes to 3 hours.

5. A method of preparing N,N'-diarylamidines which comprises the steps of mixing a primary aromatic amine with an aliphatic carboxylic acyl dicyandiamide, an acid having a dissociation constant of 1x 10-, and an inert solvent and heating the reaction mixture at an elevated temperature until an N,N-dlarylamidine is formed.

6. A method of preparing N,N'-diarylamidines which comprises the steps of mixing a primary aromatic amine with an aromatic carboxylic acyl dicyandiamide, an acid, having a dissociation constant 01' 1x10 and an inert solvent and heating the reaction mixture at an elevated temperature until an N,N'-diarylamidine is formed.

7. A method of preparing N,N-diarylamidines which comprises the steps of mixing in a solvent a carboxylic acyl dicyandiamide and an acid salt of a primary aromatic amine and heating the mixture until an N,N'-diarylamidine is formed.

JACK T. THURSTON. DANIEL E. NAGY.

December 5, 1944.

JACK T. THURSTON ET AL. It is hereby certified that error appears in the rinted specification of the above numbered patent req claim 3, for IXIS Hw with this correction the Patent Oifice.

correction as follows: 1X10"; and that the said therein that the same may conform to the record of the case in e 5, second column, line 16 otters Patent should be read Signed and sealed this 6th day of March, A. D. 1945.

[sun] LESLIE FRAZER,

Acting Commissioner of Patents. 

